Blood: Detecting leukemia 16 years in advance?

▎WuXi AppTec Content Team Editor Chronic lymphocytic leukemia (CLL) is the most common type of leukemia, usually occurs in adults over 60 years old, and the disease progresses slowly
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Monoclonal B-cell lymphocytosis (MBL) is a prodromal state of CLL that is usually detected 6 years before CLL diagnosis and can occur in up to 12% of older adults
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However, the duration of MBL and the mechanisms by which it evolves into CLL remain largely unknown
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A study recently published in BLood, a journal of the American Society of Hematology, provides important information on how the disease develops
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The study, from a team from the Department of Immunology at Erasmus Medical Center in the Netherlands, analyzed the sequencing of blood samples from patients up to 22 years before diagnosis, and the results suggest that the preclinical stage of CLL may be longer than previously thought, even in patients with poor prognosis.
This is also the case
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The findings "represent the earliest detection of CLL clonotype precursor cells," stressed Gerald Marti, MD, of the National Institutes of Health's Heart, Lung and Blood Institute (NHLBI) in a related commentary
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Screenshot source: Blood Participants in this study were drawn from the well-known EPIC (European Prospective Investigation into Cancer and Nutrition) cohort
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To gain insight into the characteristics of B cell receptors in the early stages of CLL, the research team compared the B cell receptor (BcR) immunoglobulin heavy chain (IgH) gene repertoire (gene repertoire) in blood samples from 124 CLL patients and 118 matched controls.
) were sequenced, and blood samples were taken as early as 22 years before the diagnosis of CLL or small lymphocytic leukemia (SLL)
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CLL shares the same pathological and immunophenotypic features as SLL, but CLL disease is mainly concentrated in peripheral blood, while SLL disease is mainly concentrated in lymph nodes
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The researchers observed that significant alterations in the BcR IgH gene pool were detected in the majority of patients, and the dominant clonotype frequency was significantly different in CLL patients compared with controls (54.
9% vs 0.
38%), even in lymphoid cells.
This was the case before the onset of polycytosis, and this feature was not associated with the somatic hypermutation status of clonotype IgH variable region genes
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In the 28 patients whose lymphocyte counts were measured at baseline, the data also suggested signs of pre-disease: 10 patients' samples showed evidence of lymphocytosis 8 years before CLL diagnosis
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The research team explained that this suggested that these patients were asymptomatic cases of CLL
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Next-generation sequencing results showed that up to 15 years before CLL diagnosis, 21 of 28 patients had detectable alterations in the IgH gene pool, usually in the absence of elevated lymphocyte counts
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Notably, some CLL patients requiring therapy, and clinically transformed into aggressive B-cell lymphoma, also exhibited considerable alterations in the IgH gene pool as early as 16 years before CLL diagnosis
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In addition, among 14 CLL patients, a type-specific predominant clonotype was associated with poor prognosis 16 years before diagnosis
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Patients with an IgHV-unmutated predominant clonotype before diagnosis had significantly shorter overall survival after CLL diagnosis than patients with an IgHV-mutated clonotype
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50% to 60% of patients have somatic mutations in the immunoglobulin heavy chain variable region (IgHV) gene
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CLL cells with IgHV gene mutation originate from memory B cells in the post-germinal center, and these patients progress slowly; CLL cells without IgHV gene mutation originate from primitive B cells in the pre-germinal center, and the patients progress faster and are easier to treat.
Poor response to immunochemotherapy and poor prognosis
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Twenty-two patients had samples from multiple different time points
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The data show that alterations in the BcR IgH gene pool significantly increased or remained stable at high levels over time
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Image credit: 123RF "To our knowledge, the dynamics of MBL patient progression to CLL have never been captured in such a convincing manner," the research team said, and the findings "extend current knowledge on the evolution of the IgH gene pool prior to CLL diagnosis.
, underscoring that even high-risk CLL subtypes may exhibit a prolonged indolent preclinical phase
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" The research team further noted that "a deeper elucidation of the distinction between 'progressive' MBL and 'stable' MBL would be extremely valuable.

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Nevertheless, we stress that early detection is only needed when it can provide a clear benefit to patient care
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